PROJECT SUMMARY/ABSTRACT This is a K23 award application for Dr. Santosh Murthy, a neurologist and young investigator pursuing patient-oriented clinical research on arterial thrombotic events after intracerebral hemorrhage (ICH). Dr. Murthy intends to develop his skills and expertise in three key areas: 1) advanced biostatistics and data science; 2) stroke pathophysiology, biomarker analysis, and cardiac diagnostic imaging techniques; and 3) clinical trial design and implementation. To pursue this project, Dr. Murthy has assembled a mentoring team that comprises a primary mentor, Dr. Hooman Kamel, a neurologist with expertise in stroke epidemiology and clinical trial design, and 3 co-mentors, Dr. Costantino Iadecola, a neurologist and neurobiologist with expertise in ischemic brain injury and biomarkers, Dr. Daniel Hanley, a neurologist with expertise in ICH and clinical trial design, and Dr. Monika Safford, an internist with expertise in cardiovascular epidemiology. Dr. Murthy's central hypothesis is that ICH is an independent, short-term, modifiable risk factor for arterial thromboembolism, defined as acute ischemic stroke or acute myocardial infarction. This hypothesis will be tested by pursuing three specific aims. Specific Aim 1 will test the hypothesis that the risk of arterial thromboembolism is elevated in the acute phase after ICH. This will entail performing a cohort study using data pooled from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Northern Manhattan Study (NOMAS) and the Strong Heart Study. Specific Aim 2A will test the hypothesis that baseline ICH hematoma volume is associated with clinically apparent stroke and MI. This will be tested in a secondary analysis of data from the MISTIE III trial. Specific Aim 2B will test the hypothesis that ICH hematoma volume correlates with magnetic resonance imaging (MRI) evidence of cerebral and myocardial infarcts. This aim will be tested by performing a prospective cohort study of ICH patients at New York-Presbyterian Hospital/Weill Cornell. Secondary exploratory analyses will correlate hematoma volume with known biomarkers of thrombosis. Specific Aim 3 will test the hypothesis that early use of antithrombotic medications reduces the risk of arterial thromboembolic events after ICH, even in patients without a high-risk indication for anticoagulation such as atrial fibrillation. This aim will be pursued by using claims and pharmacy data from Premier, a commercial database containing data on several thousand ICH hospitalizations across the country. The proposed research is significant because positive results would uncover ICH as a novel risk factor for subsequent arterial thromboembolic complications. Furthermore, it would provide crucial preliminary data for a randomized trial to identify optimal antithrombotic strategies after ICH. The proposed research is innovative because it seeks to shift current research and clinical practice paradigms by identifying a new class of patients who are at high risk for stroke and MI and who may benefit from existing antithrombotic medications.!